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Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7

SARS-CoV-2 mRNA vaccines, including Pfizer/Biontech BNT162b2, were shown to be effective for COVID-19 prevention, eliciting both robust antibody responses in naive individuals and boosting pre-existing antibody levels in SARS-CoV-2-recovered individuals. However, the magnitude, repertoire, and phenotype of epitope-specific T cell responses to this vaccine, and the effect of vaccination on pre-existing T cell memory in SARS-CoV-2 convalescent patients, are still poorly understood. Thus, in this study we compared epitope-specific T cells elicited after natural SARS-CoV-2 infection, and vaccination of both naive and recovered individuals. We collected peripheral blood mononuclear cells before and after BNT162b2 vaccination and used pools of 18 DNA-barcoded MHC-class I multimers, combined with scRNAseq and scTCRseq, to characterize T cell responses to several immunodominant epitopes, including a spike-derived epitope cross-reactive to common cold coronaviruses. Comparing responses after infection or vaccination, we found that T cells responding to spike-derived epitopes show similar magnitudes of response, memory phenotypes, TCR repertoire diversity, and αβTCR sequence motifs, demonstrating the potency of this vaccination platform. Importantly, in COVID-19-recovered individuals receiving the vaccine, pre-existing spike-specific memory cells showed both clonal expansion and a phenotypic shift towards more differentiated CCR7-CD45RA+ effector cells. In-depth analysis of T cell receptor repertoires demonstrates that both vaccination and infection elicit largely identical repertoires as measured by dominant TCR motifs and receptor breadth, indicating that BNT162b2 vaccination largely recapitulates T cell generation by infection for all critical parameters. Thus, BNT162b2 vaccination elicits potent spike-specific T cell responses in naive individuals and also triggers the recall T cell response in previously infected individuals, further boosting spike-specific responses but altering their differentiation state. Overall, our study demonstrates the potential of mRNA vaccines to induce, maintain, and shape T cell memory through vaccination and revaccination.

Oxygen in titanium is a potent alpha stabilizer that provides solid solution strengthening. This study presents a method of exploiting surface hardening of titanium particulate media. Hardening was measured on particulate matter and compared to a bulk specimen with nanoindentation. Thermal exposure parameters increased surface hardness from ≈ 3 GPa to over 8 GPa as measured via nanoindentation. This process produced solid solution strengthening without creating a distinct oxide layer or significant sintering of particles.

BACKGROUND AND OBJECTIVE: Both chronic and aggressive periodontal disease are associated with vitamin D deficiency. The active form of vitamin D, 1,25(OH)(2)D(3), induces the expression of the antimicrobial peptide LL-37 and innate immune mediators in cultured human gingival epithelial cells (GEC). The aim of this study was to further delineate the mechanism by which vitamin D enhances the innate defense against the development of periodontal disease (PD). MATERIALS AND METHODS: Wild-type C57Bl/6 mice were made deficient in vitamin D by dietary restriction. Cultured primary and immortalized GEC were stimulated with 1,25(OH)(2)D(3), followed by infection with Porphyromonas gingivalis, and viable intracellular bacteria were quantified. Conversion of vitamin D(3) to 25(OH)D(3) and 1,25(OH)(2)D(3) was quantified by ELISA. Effect of vitamin D on basal IL-1α expression in mice was determined by topical administration to the gingiva of wild-type mice, followed by QRT-PCR. RESULTS: Dietary restriction of vitamin D led to alveolar bone loss and increased inflammation in the gingiva in the mouse model. In primary human GEC and established human cell lines, treatment of GEC with 1,25(OH)(2)D(3) inhibited the intracellular growth of P. gingivalis. Cultured GEC expressed two 25-hydroxylases (CYP27A1 and CYP2R1), as well as 1-α hydroxylase, enabling conversion of vitamin D to both 25(OH)D(3) and 1,25(OH)(2)D(3). Topical application of both vitamin D(3) and 1,25(OH)(2)D(3) to the gingiva of mice led to rapid inhibition of IL-1α expression, a prominent proinflammatory cytokine associated with inflammation, which also exhibited more than a two-fold decrease from basal levels in OKF6/TERT1 cells upon 1,25(OH)(2)D(3) treatment, as determined by RNA-seq. CONCLUSION: Vitamin D deficiency in mice contributes to PD, recapitulating the association seen in humans, and provides a unique model to study the development of PD. Vitamin D increases the activity of GEC against the invasion of periodontal pathogens, and inhibits the inflammatory response, both in vitro and in vivo. GEC can convert inactive vitamin D to the active form in situ, supporting the hypothesis that vitamin D can be applied directly to the gingiva to prevent or treat periodontal disease.

It is estimated that 250,000 to 650,000 individuals worldwide die each year from seasonal influenza A virus (IAV) infections. Current vaccines provide little protection against newly emerging strains. Thus, considerable effort is focused on enhancing the generation of broadly reactive IAV antibodies in order to develop a universal IAV vaccine. However, broadly reactive IAV antibodies are rare and the factors that limit their generation are not completely understood. Our data disprove the prevailing hypothesis that broadly reactive IAV antibodies are uncommon due to competition in the germinal centers with antibodies specific for the variable, hemagglutinin (HA) head. Understanding the factors that constrain development of antibodies specific for conserved regions of IAV is imperative for developing an effective universal IAV vaccine, which could potentially circumvent a catastrophic pandemic. These findings are significant as they highlight the importance of investigating other mechanisms that contribute to the paucity of broadly reactive IAV antibodies., Enhancing the generation of broadly reactive antibodies against influenza A virus (IAV) is a pertinent goal toward developing a universal IAV vaccine. While antibodies that bind conserved IAV epitopes have been identified in humans, antibodies specific for the variable epitopes are much more prevalent than antibodies recognizing conserved epitopes. It is important to define the factors that limit the generation of broadly reactive IAV antibodies in order to develop an effective universal IAV vaccine. The predominant theory is that competition within germinal centers favors the synthesis of high-affinity antibodies specific for the variable region of the virus, and limits antibodies specific for conserved IAV epitopes. Here, we show that reducing germinal center formation and removing competition with high-affinity antibodies was not sufficient to increase broadly reactive IAV antibodies or enhance protection against distinct IAV subtypes. These data disprove the prevailing hypothesis that broadly reactive IAV antibodies are rare due to competition within germinal centers, and reveal the critical need to further investigate factors that limit broadly reactive IAV antibodies. Additionally, our data show that IAV-specific IgM antibodies persist in mice in the absence of germinal centers, highlighting the protective capacity of germinal center-independent IgM antibodies, which are not typically considered when testing correlates of protection, and offer an alternate target for delivering a universal IAV vaccine.

Enhancing the generation of broadly reactive influenza antibodies is a pertinent goal towards developing a universal influenza vaccine. While antibodies that bind conserved influenza epitopes have been identified in humans, the frequency of these antibodies is typically very low. The predominant theory is that antibodies specific for conserved influenza epitopes are limited in germinal centers by competition with high affinity antibodies specific for the variable region of the virus. Here, we show that reducing germinal center formation and removing competition with high affinity antibodies was not sufficient to increase broadly reactive influenza antibodies or enhance protection against distinct influenza subtypes. These data disprove the prevailing hypothesis that broadly reactive influenza antibodies are rare due to competition in germinal centers. Additionally, levels of IgM antibodies specific for the variable region of HA persisted in mice in the absence of germinal centers, further demonstrating that immunodominance can be established independent of germinal centers. Our data also highlight the protective capacity of germinal center-independent IgM antibodies, which are not typically considered when testing correlates of protection, and offer an alternate target for delivering a universal influenza vaccine.IMPORTANCEIt is estimated that 250,000 – 650,000 individuals worldwide die each year from seasonal influenza infections. Current vaccines provide little protection against newly emerging strains. Thus, considerable effort is focused on enhancing the generation of broadly reactive influenza antibodies in order to develop a universal influenza vaccine. However, broadly reactive antibodies are rare and the factors that limit their generation are not completely understood. Our data disprove the prevailing hypothesis that broadly reactive influenza antibodies are rare due to completion in the germinal centers with antibodies to the variable HA head. Understanding the factors limiting antibodies specific for conserved regions of the influenza virus is imperative for developing a universal vaccine, which could potentially circumvent a global pandemic

SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine., Analysis of draining lymph nodes of individuals vaccinated BNT162b2 mRNA vaccine against SARS-CoV-2 identifies viral spike-specific follicular helper CD4+ T cells that persist for months and contribute to long-term immunity.

SARS-CoV-2 infection causes diverse outcomes ranging from asymptomatic infection to respiratory distress and death. A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoV) impacts susceptibility to SARS-CoV-2 infection or immunity following infection and vaccination. Therefore, we analyzed samples from the same individuals before and after SARS-CoV-2 infection or vaccination. We found hCCCoV antibody levels increase after SARS-CoV-2 exposure, demonstrating cross-reactivity. However, a case-control study indicates baseline hCCCoV antibody levels are not associated with protection against SARS-CoV-2 infection. Rather, higher magnitudes of pre-existing betacoronavirus antibodies correlate with more SARS-CoV-2 antibodies following infection, an indicator of greater disease severity. Additionally, immunization with hCCCoV spike proteins before SARS-CoV-2 immunization impedes generation of SARS-CoV-2 neutralizing antibodies in mice. Together, these data suggest pre-existing hCCCoV antibodies hinder SARS-CoV-2 antibody-based immunity following infection and provide insight on how pre-existing coronavirus immunity impacts SARS-CoV-2 infection, which is critical considering emerging variants., Graphical Abstract, A major unresolved question is whether prior immunity to endemic, human common cold coronaviruses (hCCCoV) impacts susceptibility to SARS-CoV-2 infection. Lin et al. analyze hCCCoV antibodies in the same individuals before and after SARS-CoV-2 infection, finding pre-existing betacoronavirus antibodies may hinder SARS-CoV-2 effective immunity following infection.

To date, Zn has not been used as an alloying addition in structural Ti alloys. The main obstacle has been the disparity between their melting and vaporization temperatures. A novel processing technique was developed to create a Ti-Zn compound. The equilibrium phases and microstructures were studied by electron microscopy and x-ray diffraction techniques. Results show the presence of pearlitic domains of α-Ti (hexagonal closed packed crystal structure) and Ti 2 Zn (body center tetragonal structure) in regions that have a near eutectoid composition. Solutionizing and water quenching results in the formation of martensite along with intermetallic laths, suggesting that the eutectoid transformation is active.

Advanced manufacturing approaches, including additive manufacturing (i.e., “3D printing”) of metallic structures requires a change to qualification strategies. One approach, informed qualification, integrates modeling strategies to make predictions of material characteristics, including the prediction of tensile properties for given chemistries and microstructures. In this work, constitutive equations are developed and presented that can predict the yield strength of additively manufactured Ti-6Al-4V subjected to one of three different heat-treatments: a stress relief anneal in the α+β phase field; a hot isostatic press treatment in the α+β phase field; and a β-anneal. The equations are nominally identical, though different strengthening mechanisms are active according to subtle microstructural differences. To achieve an equation that can predict the yield strength of the material, it is also necessary to include an assessment of dramatic reduction in the tensile strength due to texture (i.e., a “knock-down” effect). This has been experimentally measured, and included in this paper. The resulting predictions of yield strength are generally within 5% of their experimentally measured values.

It is necessary to better understand the composition–processing–microstructure relationships that exist for materials produced by additive manufacturing. To this end, Laser Engineered Net Shaping (LENS™), a type of additive manufacturing, was used to produce a compositionally graded titanium binary model alloy system (Ti-xW specimen (0 ≤ x ≤ 30 wt pct), so that relationships could be made between composition, processing, and the prior beta grain size. Importantly, the thermophysical properties of the Ti-xW, specifically its supercooling parameter (P) and growth restriction factor (Q), are such that grain refinement is expected and was observed. The systematic, combinatorial study of this binary system provides an opportunity to assess the mechanisms by which grain refinement occurs in Ti-based alloys in general, and for additive manufacturing in particular. The operating mechanisms that govern the relationship between composition and grain size are interpreted using a model originally developed for aluminum and magnesium alloys and subsequently applied for titanium alloys. The prior beta grain factor observed and the interpretations of their correlations indicate that tungsten is a good grain refiner and such models are valid to explain the grain-refinement process. By extension, other binary elements or higher order alloy systems with similar thermophysical properties should exhibit similar grain refinement.

Additive manufacturing (AM) processes have many benefits for the fabrication of alloy parts, including the potential for greater microstructural control and targeted properties than traditional metallurgy processes. To accelerate utilization of this process to produce such parts, an effective computational modeling approach to identify the relationships between material and process parameters, microstructure, and part properties is essential. Development of such a model requires accounting for the many factors in play during this process, including laser absorption, material addition and melting, fluid flow, various modes of heat transport, and solidification. In this paper, we start with a more modest goal, to create a multiscale model for a specific AM process, Laser Engineered Net Shaping (LENS™), which couples a continuum-level description of a simplified beam melting problem (coupling heat absorption, heat transport, and fluid flow) with a Lattice Boltzmann-cellular automata (LB-CA) microscale model of combined fluid flow, solute transport, and solidification. We apply this model to a binary Ti-5.5 wt pct W alloy and compare calculated quantities, such as dendrite arm spacing, with experimental results reported in a companion paper.

Oral epithelial cells (OEC) represent the first site of host interaction with viruses that infect the body through the oral route, however their innate antiviral defense mechanisms have yet to be defined. Previous studies have determined that OEC express pathogen-, damage- or danger-associated molecular patterns (PAMPs, or DAMPs), but their expression of key antiviral innate immune mediators, including type I interferons (type I IFN) and interferon-stimulated genes (ISGs) has not been studied extensively. We used the oral keratinocyte cell line, OKF6/TERT1 in the presence and absence of the viral mimics poly(I:C) and unmethylated CpG DNA, to define the expression of type I IFN and ISGs. We identified the basal expression of novel type I IFN genes IFNE and IFNK, while IFNB1 was induced by viral mimics, through the nuclear translocation of IRF3. Numerous ISGs were expressed at basal levels in OEC, with an apparent correlation between high expression and antiviral activity at the earlier stages of viral infection. Stimulation of OECs with poly(I:C) led to selective induction of ISGs, including MX1, BST2, PML, RSAD2, ISG15 and ZC3HAV1. Together, our results demonstrate that OECs exhibit a robust innate antiviral immune defense profile, which is primed to address the wide variety of pathogenic viruses that are transmitted orally.

Fe-3Si-3Al and Fe-4Si-4Cr (wt%) experimental alloys were processed to assess the electrical resistivity and workability effects of substituting Al and Cr for Si in high-Si electrical steel alloys. The experimental alloys were made by arc melting, and processed by hot rolling and cold rolling to produce strips. Samples were characterized by means of metallography, hardness, workability and resistivity. Results showed that the two alloys could be rolled down to 200 µm thickness (90% hot-rolled reduction and 80% cold rolled reduction) without crack formation in the strips. Hardness in the annealed condition and electrical resistivity were 228 HV/74 µΩ cm and 243 HV/85 µΩ cm, respectively, for the Fe-3Si-3Al and for Fe-4Si-4Cr alloys. The resistivity measured for Fe-4Si-4Cr was higher than the resistivity reported for the benchmark high-Si alloy, Fe-6.5Si. Both experimental alloys showed improvement on the workability compared to Fe-6.5Si since there was no edge cracking on the cold-rolled strips up to 80% reduction, and the hardness was approximately 35% lower.

Laser Engineered Net Shaping (LENS™) was used to produce a compositionally graded Ti-xMo (0 ≤ x ≤ 12 wt %) specimen and nine Ti-15Mo (fixed composition) specimens at different energy densities to understand the composition–processing–microstructure relationships operating using additive manufacturing. The gradient was used to evaluate the effect of composition on the prior-beta grain size. The specimens deposited using different energy densities were used to assess the processing parameters influence the microstructure evolutions. The gradient specimen did not show beta grain size reduction with the Mo content. The analysis from the perspective of the two grain refinement mechanisms based on a model known as the Easton & St. John, which was originally developed for aluminum and magnesium alloys shows the lower bound in prior-beta grain refinement with the Ti–Mo system. The low growth restriction factor for the Ti-Mo system of Q = 6,5C0 explains the unsuccessful refinement from the solute-based mechanism. The energy density and the grain size are proportional according to the results of the nine fixed composition specimens at different energy densities. More energy absorption from the material represents bigger molten pools, which in turn relates to lower cooling rates.

A direct comparison between the oxidation behavior of Ti-6Al-4V and Ti-6Al-4V + 1B has been conducted to elucidate whether the addition of boron to Ti-6Al-4V impacts the oxidation behavior. Industrially prepared sheet of Ti-6Al-4V and Ti-6Al-4V + 1B were oxidized at temperatures between 650 and 950 °C for holding times of 25 and 50 h. Weight-gain measurements and characterization of surface and near-surface microstructures showed that the addition of 1 wt% B increased the material’s oxidation resistance. Additionally, the ingress of oxygen tends to decrease the solubility of other alloying species in α-Ti and leads to the formation of a distinctive and atypical microstructure with a distinct morphology.

Oral epithelial cells (OECs) represent the first line of defense against viruses that are spread via saliva, including Kaposi's sarcoma-associated herpesvirus (KSHV). Infection of humans by KSHV and viral pathogenesis begins by infecting OECs. One method OECs use to limit viral infections in the oral cavity is the production of antimicrobial peptides (AMPs), or host defense peptides (HDPs). However, no studies have investigated the antiviral activities of any HDP against KSHV. The goal of this study was to determine the antiviral activity of one HDP, LL-37, against KSHV in the context of infecting OECs. Our results show that LL-37 significantly decreased KSHV's ability to infect OECs in both a structure- and dose-dependent manner. However, this activity does not stem from affecting OECs, but instead the virions themselves. We found that LL-37 exerts its antiviral activity against KSHV by disrupting the viral envelope, which can inhibit viral entry into OECs. Our data suggest that LL-37 exhibits a marked antiviral activity against KSHV during infection of oral epithelial cells, which can play an important role in host defense against oral KSHV infection. Thus, we propose that inducing LL-37 expression endogenously in oral epithelial cells, or potentially introducing as a therapy, may help restrict oral KSHV infection and ultimately KSHV-associated diseases.

To understand the role of composition in the oxidation behavior of Ti–Mo system and to evaluate the extent of oxygen ingress into the metal substrate during high temperature exposure, a compositionally graded Ti–xMo specimen (0 ≤ x ≤ 12 wt% Mo) was prepared using an additive manufacturing technique, solutionized and then subjected to oxidation tests at 650 °C for different exposure times. The depth of oxygen diffusion, across the composition range, was assessed via change in the local hardness and the results were coupled with quantitative measurement of the oxygen concentration. The concentration of O in the α phase was reduced by 90 % after a short distance of 16 μm from the metal/oxide interface while it remained more or less the same in β phase. The solubility of Mo in α phase also approached zero near the surface as O changed the partition coefficient of this element between α and β phases. It was shown that the addition of Mo reduces the solubility of O in the metal substrate which in turn retards the transition point from parabolic to the linear oxidation stage.

Poor oxidation performance of Ti-based alloys is an important life-limiting factor for high temperature applications. In this paper, a combinatorial approach is used to investigate systematically the influence of composition and time on the oxidation of Ti–Cr system. A compositionally graded Ti– x Cr specimen (0 ⩽ x ⩽ 40 wt%) was prepared and oxidized at 650 °C. The structure and composition of the oxide and near-surface region were studied and a critical composition of ∼20 wt% Cr was identified above which the oxidation resistance is enhanced. Below the critical composition transition to a rapid breakaway oxidation was observed for extended exposure times.

One key aspect of any integrated computational materials engineering approach is the integration of experiments that provide critical information for the modeling activities. This article describes, using case studies, three examples of critical experiments that have been conducted in an integrated fashion with modeling activities for titanium alloys, providing valuable information in an accelerated manner. The first has been used to identify key microstructural features associated with fracture toughness in Ti-6Al-4V and integrates artificial neural networks and various experimental techniques. The second is associated with defect accumulation in highly constrained titanium structures and integrates a highly innovative characterization technique (precession electron diffraction) and dislocation dynamics. The third is a high-throughput combinatorial technique to understand the oxidation behavior of titanium alloys and couples the experimental effort with the CALPHAD approach.

Alkali-activated concrete (AAC) has been commercialized as a low-CO2 construction material, but its adoption still faces several challenges, including standardization, lack of a dedicated supply chain, limited service track record, and the question of whether laboratory durability testing can predict service life. This paper outlines how using different precursors leads to the formation of different AAC phase assemblages, and how AAC can be recognized in standards using a performance-based approach independent of binder chemistry. Microstructural assessment of pastes, strength development, water permeability, and chloride migration of two AACs (100% slag and 1:1 slag:fly ash) are presented, and compared to Portland cement concrete. Manipulation of binder chemistry leads to differences in the properties of the AACs; however, both AACs assessed exhibited technical benefits in a performance-based comparison. AACs can meet the requirements of the equivalent performance concept, independent of the binder chemi...

Mechanical strength, water and chloride permeability of alkali activated slag mortar and concretes with partial fly ash substitution are investigated. Volume of permeable voids (VPV) and sorptivity testing show that alkali-activated materials exhibit higher water absorption than OPC-based samples, and increasing fly ash addition leads to reduced mechanical strength and increased water absorption. Conversely, chloride permeability testing by the NordTest NT Build 492 standard accelerated method, and by chloride ponding (ASTM C1543), shows that the diffusion of chloride in alkali-activated binders is much less than in OPC binders. This divergence between measured water uptake and chloride permeability in alkali-activated specimens is attributed largely due to the specified standard preconditioning (drying) of the samples prior to water absorption testing due to the difference in water environments as a function of slag/fly ash ratio. Drying is likely to be inducing desiccation and consequent microcracking of slag-based binding gels, while less disturbance occurs in a fly ash geopolymer gel. The chemistry of the binding gels in these alkali-activated systems significantly controls the mass and ionic transport in chloride-containing environments. Although higher porosity was measured by these standards, a denser Al-substituted calcium silicate hydrate (C–A–S–H) gel contributes to a higher mechanical strength, and durability under chloride exposure. The inclusion of fly ash promotes the formation of more porous sodium aluminosilicate (N–A–S–H) type gels, reducing the resistance to transport.

Binders formed through alkali-activation of slags and fly ashes, including ‘fly ash geopolymers’, provide appealing properties as binders for low-emissions concrete production. However, the changes in pH and pore solution chemistry induced during accelerated carbonation testing provide unrealistically low predictions of in-service carbonation resistance. The aluminosilicate gel remaining in an alkali-activated slag system after accelerated carbonation is highly polymerised, consistent with a decalcification mechanism, while fly ash-based binders mainly carbonate through precipitation of alkali salts (bicarbonates at elevated CO2 concentrations, or carbonates under natural exposure) from the pore solution, with little change in the binder gel identifiable by nuclear magnetic resonance spectroscopy. In activated fly ash/slag blends, two distinct gels (C–A–S–H and N–A–S–H) are formed; under accelerated carbonation, the N–A–S–H gel behaves comparably to fly ash-based systems, while the C–A–S–H gel is decalcified similarly to alkali-activated slag. This provides new scope for durability optimisation, and for developing appropriate testing methodologies.

Lethal systemic fungal infections of Candida species are increasingly common, especially in immune compromised patients. By in vitro screening of small molecule mimics of naturally occurring host defense peptides (HDP), we have identified several active antifungal molecules, which also exhibited potent activity in two mouse models of oral candidiasis. Here we show that one such compound, C4, exhibits a mechanism of action that is similar to the parent HDP upon which it was designed. Specifically, its initial interaction with the anionic microbial membrane is electrostatic, as its fungicidal activity is inhibited by cations. We observed rapid membrane permeabilization to propidium iodide and ATP efflux in response to C4. Unlike the antifungal peptide histatin 5, it did not require energy-dependent transport across the membrane. Rapid membrane disruption was observed by both fluorescence and electron microscopy. The compound was highly active in vitro against numerous fluconazole-resistant clinical isolates of C. albicans and non-albicans species, and it exhibited potent, dose-dependent activity in a mouse model of invasive candidiasis, reducing kidney burden by three logs after 24 hours, and preventing mortality for up to 17 days. Together the results support the development of this class of antifungal drug to treat invasive candidiasis.

The carbonation resistance of alkali-activated binders is often tested via accelerated test protocols designed for Portland cements, without questioning whether the tests replicate the mechanisms observed in service. Thus, validation of accelerated methods is required to enable realistic prediction of material performance. Changes in pore solution equilibria cause the formation of sodium bicarbonates during accelerated carbonation, compared with hydrous sodium carbonates in natural carbonation. This shifts the carbonation mechanism to favour more rapid reaction progress, to give a higher apparent degree of acceleration (compared to natural conditions) than in Portland cements. The pore solution pH under accelerated carbonation is significantly lower than at natural CO2 concentrations, leading to a falsely short predicted service life (time to expected corrosion of embedded steel), as natural CO2 concentrations appear not to reduce the pH below 10. Thus, accelerated carbonation testing is unduly aggressive towards alkali-activated binders, and test results must be cautiously interpreted.

Concentrated sodium silicate solutions of modulus (SiO2/Na2O molar ratio) close to 1.0 are well-known to precipitate hydrous sodium metasilicate crystals; this hinders their industrial-scale utilization in applications including geopolymer concrete synthesis. The substitution of 20–50% of the sodium by potassium in such solutions is seen to greatly reduce or prevent this precipitation, on a time scale of up to 7 years. A potassium substitution rate of 20% does not entirely eliminate precipitation, but does reduce it very significantly; 50% substitution does eliminate precipitation, although the viscosity of the solution increases notably at this level of substitution. This substitution provides a relatively low-cost means of extending the shelf life of concentrated low-modulus alkali silicate solutions for large-scale utilization in the production of geopolymer concretes and in other applications.

Portland cement production has been identified as a primary contributor to the world’s Greenhouse gas emissions, calculated at around 5–8% of all manmade emissions worldwide. The majority of these emissions are inherent to the chemistry of cement and the high-temperature processing required for its synthesis, and so can only be avoided by radical changes in construction materials chemistry and synthesis pathways. Inorganic polymer (including “geopolymer”) binders provide an alternative to traditional cements with approximately 80% less CO2 emissions, and are derived from industrial waste materials such as fly ash and metallurgical slags, which additionally provide a means of valorizing these wastes. This paper reviews the technical and commercial factors driving the growing commercial adoption of geopolymer technology, and explains that an understanding of the chemistry and mechanisms of geopolymer synthesis is pivotal for the optimal mix design of “green” concretes in industry. Demand pull by a carbon conscious market at a time of growing public awareness of climate change continues to be the key driver for the short term adoption of geopolymer concrete. A detailed chemical understanding of the properties of geopolymers, such as setting time, workability and durability, plays an enabling role in the commercialization process.

The Time Between Photons theory (hereafter TBP) is applied to the evaluation of the lifetime of phosphors employed in the Ion Photon Emission Microscope (IPEM). IPEM allows Radiation Effects Microscopy (REM) without focused ion beams and appears to be the best tool for the radiation hardness assessment of modern integrated circuit at cyclotron energies. IPEM determines the impact point of a single ion onto the sample by measuring the light spot produced on a thin phosphor layer placed on the sample surface. The spot is imaged by an optical microscope and projected at high magnification onto a Position Sensitive Detector (PSD). Phosphors, when excited by an ion, emit photons with a particular lifetime, which is important to evaluate. We measured the statistical distribution of the Time Between consecutive detected Photons (TBP) for several phosphors and have been able to link it to their lifetime employing a theory that is derived in this paper. The single-photon signals are provided by the IPEM-PSD, or faster photomultipliers when high-speed materials had to be assessed.

Microelectronic devices in satellites and spacecraft are exposed to high energy cosmic radiation. Furthermore, Earth-based electronics can be affected by terrestrial radiation. The radiation causes a variety of Single Event Effects (SEE) that can lead to failure of the devices. High energy heavy ion beams are being used to simulate both the cosmic and terrestrial radiation to study radiation effects and to ensure the reliability of electronic devices. Broad beam experiments can provide a measure of the radiation hardness of a device (SEE cross section) but they are unable to pinpoint the failing components in the circuit. A nuclear microbeam is an ideal tool to map SEE on a microscopic scale and find the circuit elements (transistors, capacitors, etc.) that are responsible for the failure of the device. In this paper a review of the latest radiation effects microscopy (REM) work at Sandia will be given. Different SEE mechanisms (Single Event Upset, Single Event Transient, etc.) and the methods to study them (Ion Beam Induced Charge (IBIC), Single Event Upset mapping, etc.) will be discussed. Several examples of using REM to study the basic effects of radiation in electronic devices and failure analysis of integrated circuits will be given.

Rare earth doped yttrium oxide (yttria) and silicate, Y{sub 2}O{sub 3}:Eu and Y{sub 2}SiO{sub 5}:Tb, are the most promising phosphors for advanced devices such as flat panel field-emission-displays. However, their light yield for electron excitation has proven to be lower than that predicted by early models. New experimental data are needed to improve the theoretical understanding of the cathodoluminescence (CL) that will, in turn, lead to materials that are significantly brighter. Beside the existing CL and photo luminescence (PL) measurements, one can provide new information by studying ion-induced luminescence (IL). Ions penetrate substantially deeper than electrons and their light yield should therefore not depend on surface effects. Moreover, the energy density released by ions can be much higher than that of electrons and photons, which results in possible saturation effects, further testing the adequacy of models. We exposed the above yttrium compounds to three ion beams, H (3 MeV), C (20 MeV), Cu (50 MeV), which have substantially different electronic stopping powers. H was selected to provide an excitation close to CL, but without surface effects. The C and Cu allowed an evaluation of saturation effects because of their higher stopping powers. The IL experiments involved measuring the transient lightmore » intensity signal radiating from thin phosphor layers following their exposure to {approx}200 ns ion beam pulses. We present the transient yield curves for the two materials and discuss a general model for this behavior.« less

Spatial distributions in ion micro-beam and IBA experimental practice are regularly characterized through the parameters of FWHM and tail area percentage (TF, tail fraction). Linear and stationary transducer theory allows these distributions to be described in the Fourier-dual frequency space, and provides an indirect method to evaluate them through measurement of the modulation transfer function (MTF). We suggest direct measurement of MTF by employing bar pattern grids, similar to those used for calibration of radiological equipment. Assuming spatial distributions of the form exp(−(|αx|)η), we are able to relate the MTF measurements to the more popular FWHM and TF. This new approach to determine spatial resolution can become a standard for use by the micro-beam community.

Elongated, discontinuous defects provide strong vortex pinning and a corresponding large increase in critical current density in highly anisotropic Tl/sub 2/Ba/sub 2/CaCu/sub 2/O/sub x/ (Tl-2212) thin films. We generate controlled, amorphous damage regions in Tl-2212 thin films ranging from short, discontinuous defects to continuous linear tracks using Au ion irradiation with incident energies of 30, 60 and 88 MeV. High-resolution TEM images and magnetization data allow correlation of microstructural damage with changes in the superconducting properties. Furnace annealing of an irradiated film shows that the enhanced pinning is stable to above 600/spl deg/C.

In the context of a Report such as this, it is of immense value to be able to provide tangible examples of structures and applications in which alkali-activated concretes have been utilised throughout the past decades. A detailed outline of the utilisation of AAM concretes in the former Soviet Union and in China is given in Chap. 12 of the book by Shi, Krivenko and Roy [1], and this chapter will briefly describe some of the applications mentioned in that (more extensive) document, along with applications elsewhere in the world where AAMs have been utilised on a significant scale in the construction of buildings and other civil infrastructure components. An overview of developments and applications in the former USSR has also been presented by Brodko [2] and by Krivenko [3]. Each project reported in this chapter involves at least pilot-scale, and in some cases full commercial-scale, production of alkali-activated concretes utilising largely standard concrete mixing and placement equipment and labour, indicating that these materials are both accessible and useful on this length scale, given sufficient expertise in mix design based on locally available precursors. In the former USSR in particular, slags obtained from local iron production facilities were used in each of the different locations in which the concretes were produced, and activators were sourced in large part from locally available alkaline industrial waste streams.

The key outcome of RILEM TC 224-AAM has been the development of a conceptual framework from which the discussion of standardisation of alkali-activated binders and concretes can proceed. There has been agreement from the members of the TC that a performance-based approach to both materials formulation (as described in Chap. 7 of this report) and testing (as outlined in Chaps. 8,9, and 10) is essential in enabling the scale-up of alkali-activation as a method of concrete production in the global context. However, it is essential to proceed with a degree of conservatism, to avoid becoming ‘the next high-alumina cement problem’ through use of a material in environments and/or systems where it is not fit for purpose. So, it is critical that standards development is conservative to ensure that due care is taken, and to make sure that poor-quality AAM products, and/or products used in unsuitable applications, do not ruin the global reputation of the technology. A key discussion which occupied much of the time of the TC was the issue of how to achieve this – and the conclusion reached was that the use of strict performance criteria (and maybe even criteria which seem excessively strict until a higher degree of certainty regarding performance levels can be reached), and with good scientific foundations, must underpin any testing method applied to these materials.

Heavy Ion Backscattering Spectrometry (HIBS) is an ion beam analysis tool for measuring very low levels of surface contamination. HIBS uses low-energy (100–200 keV), heavy ions (C + . N + ) for analysis combined with a thin carbon foil to range out the increased backscattering yield from the substrate. A new HIBS system has been built at Sandia National Laboratories under a cooperative research agreement with Sematech, which was made available as a user facility for Si wafer contamination analysis beginning in July 1995. A number of factors have influenced the detection limits which are being achieved, including detector efficiency; choice of beam species and energy, sputtering by the incident beam, and spectral background due to multiple scattering and random coincidences. Because of the increased sensitivity of this new system, we have identified sources of background which had not been a problem in a research prototype. These include problems with beam scattering in the chamber, molecular contamination in O and N beams, and forward scattering of H by the incident beam. In its first tests the system has demonstrated detection limits of ∼ 6 × 10 9 atoms/cm 2 for Fe to ∼ 3×10 8 atoms/cm 2 for Au on Si.

Low‐energy ion bombardment of the Ge(001)‐(2×1) surface produces surface point defects, which are detected and quantified using in situ reflection high‐energy electron diffraction. Surface defect production rates are determined for a range of ion energies and ion masses. At low substrate temperatures (T≊−100 °C), copious production of surface defects is observed, with defect yields as high as 20–30 defects per ion for 500 eV Ar and Xe bombardment. The observed He surface defect yields exceed the surface yield predicted by binary collision simulations, indicating that defects created in the subsurface region migrate to the surface for these conditions. The observed surface defect yield is reduced at elevated substrate temperatures. Based on a simple model this reduction is attributed to surface recombination of point defects created within the same cascade. A constant surface defect yield is reached at temperatures greater than 100 °C which is consistent with the net defect production due to the vacancies ...

Molecular dynamics (MD) calculations of the bulk threshold displacement energies in single crystal silicon are carried out using the Tersoff potential. The threshold values are angularly dependent and typically vary from 10 to 20 eV for initial primary recoil momentum vectors near open directions in the lattice. An analytic representation of the angular dependence of the threshold values about the and is developed to facilitate comparison with experiment

An analytical expression and an integral representation are presented for the contribution, Y(n) = ϵ(n)Δωn, of n-event multiple scattering chains to the observed backscattering spectrum in heavy-ion backscattering (HIBS) measurements. The approximations introduced in deriving the results are chosen such that an upper limit is placed on Y(n) by the expressions. The Rutherford elastic scattering cross section is used to describe individual collisions between incident projectiles and target atoms. Screening of the Rutherford scattering cross section is included in an approximate fashion which maintains the upper limit estimate. Inelastic energy loss between collision events is assumed proportional to the projectile velocity. Specific application of these expressions is made to HIBS detection of trace amounts of heavy atom impurities on a Si surface by 200–400 keV C+ beams. The predicted multiple scattering background for this application is compared with the predicted single scattering signal for 1010 at./cm2 of Fe, Cu, Zr, Sn, or Au, as a surface impurity. The comparison shows that the multiple scattering background poses no barrier to extending the sensitivity of HIBS detection of impurities in this mass range to levels as low as 108 at./cm2 for the upper part of the energy range considered. Comparison of calculations with and without screening included show that the screening of the Rutherford cross section by atomic electrons is a significant factor in preventing multiple scattering effects from interfacing with HIBS spectrometry at impurity levels in the 1010 at./cm2 range.

A 42 kDa DNA-binding protein is associated with DNA polymerase-alpha-primase in pea (Pisum sativum). In a previous publication it was shown that the protein has strong preference for ds-ss junctions in DNA, including the cohesive termini generated by restriction endonucleases. In this paper it is shown that when the DNA-binding protein is added back to polymerase-primase, the protein stimulates the activity of the polymerase. The stimulation is particularly marked when M13 DNA, primed with a single sequencing primer or primed with oligoribonucleotides by the polymerase's associated primase activity, is used as a template. The stimulation of polymerase activity is not caused by an increase in processivity. These data lead to the suggestion that the 42 kDa DNA-binding protein is a primer-recognition protein.

Radiation Effects Microscopy is an extremely useful technique in failure analysis of electronic parts used in radiation environment. It also provides much needed support for development of radiation hard components used in spacecraft and nuclear weapons. As the IC manufacturing technology progresses, more and more overlayers are used; therefore, the sensitive region of the part is getting farther and farther from the surface. The thickness of these overlayers is so large today that the traditional microbeams, which are used for REM are unable to reach the sensitive regions. As a result, higher ion beam energies have to be used (> GeV), which are available only at cyclotrons. Since it is extremely complicated to focus these GeV ion beams, a new method has to be developed to perform REM at cyclotrons. We developed a new technique, Ion Photon Emission Microscopy, where instead of focusing the ion beam we use secondary photons emitted from a fluorescence layer on top of the devices being tested to determine the position of the ion hit. By recording this position information in coincidence with an SEE signal we will be able to indentify radiation sensitive regions of modern electronic parts, which will increase the efficiency ofmore » radiation hard circuits.« less

A distinctly new model for bulk hydrogen recombination in hydrogen implanted graphite is presented. The model considers deep H-atom traps (2.8 eV), but the thermal properties of the recombination and release are determined by shallow (few tenths eV) localized vibrational modes within the trapping potential well in combination with tunneling between trap sites. Four sources of hydrogen recombination are considered: i) direct recombination of hydrogen implanted into a hydrogen rich region, ii) recombination of hydrogen displaced from traps by the incident beam, iii) recombination of hydrogen which tunnels through the potential barrier separating adjacent trap sites, and iv) diffusive recombination. A mechanism for thermal relaxation of the localized vibrational modes is included in the model. Interaction of the incident beam with both trapped atomic H and diffusing molecular H 2 is considered in the model. Various implantation parameters and interaction cross sections required by the model are evaluated with TRIMRC calculations. Other parameters are obtained from the literature or from fits to experimental data. The model is found to give good agreement with experimental inventory versus isochronal anneal temperature, saturation inventory versus implantation temperature, and ion-induced release versus ion fluence measurements. Experiments for confirming the model are suggested.

Surface displacements due to low-energy (100–300 eV) Xe ion bombardment of the Ge(001) 2 × 1 reconstructed surface are investigated by in-situ RHEED measurements of surface roughening. The near-exponential decay in RHEED intensity due to displacements of Ge atoms at the surface is shown to depend sensitively on the Xe energy and flux. Iso-damage rate curves at 100°C are used to establish a fixed amount of defect annealing and to determine the number of surface displacements per Xe as a function of Xe energy. The calculated number of near-surface displacements per Xe exhibits a similar energy dependence. Comparison of experiment and calculation indicates an efficiency for the production of stable surface defects of about 50% at a temperature of 100°C and a damage rate of 2 × 10 12 displacements/cm 2 s. Results indicate this new approach will allow the threshold energies for surface atom displacements to be measured.